This proposal is designed to investigate the interactions between lithium and the cholinergic system in order to clarify the biochemical mechanisms of the therapeutic effects of lithium. Two projects are proposed: one examines the cholinergic system in human blood and the other utilizes rat brain. The cholinergic system in human blood will be examined by measuring choline levels in plasma and erythocytes, cholinesterase activity in plasma and erythrocytes and choline transport in erythrocytes and the release of choline from lipids. These measurements will be made in controls, bipolar manic-depressive (lithium-free and lithium treated), unipolar depressives and schizophrenic patients. Of special interest is the inhibitory effect of lithium on erythrocyte choline transport which results in a 10 to 50-fold increase in the erythrocyte choline concentration. We will investigate the mechanism of this effect by studying choline flux in erythrocyte ghosts, young and old erythrocytes and mixtures of control and lithium-treated erythrocyters and plasma. Rates will be treated with lithium alone and in combination with an anticholines-terase (eserine), and agonist (oxotremorine) and a precursor (phosphatidyl-choline). We will investigate the effects of these treatments on 32Pi incorporation into phospholipids, high affinity choline uptake in synaptosomes, 14C-glucose utilization in brain slices, choline acetyltransferase activity and muscarinic receptors. These experiments are designed to more clearly define the effects of lithium on central cholinergic activity and to help explain the production of seizures and brain damage resulting from co-administration of these drug. Results from this investigation should increase our understanding of the cholinergic system in blood and brain, clarify the therapeutic mechanism of action of lithium and provide information about the underlying biochemical disorders in certain neuropsychiatric disorders.